The role of sex differences in cardiovascular, metabolic, and immune functions in health and disease: a review for "Sex Differences in Health Awareness Day".

Sexual dimorphism is a fundamental characteristic of the anatomy and physiology of animals and humans, yet biomedical research has largely ignored these phenomena in the study of health and disease, despite early studies in the eighteenth and nineteenth centuries that demonstrated the importance of sex differences. With the explosive growth of biomedical research following World War II, especially in the 1970s through the 1990s, preclinical and clinical studies led to a greater recognition of sex differences in physiological function, particularly the significant disparities in the incidence of and mortality from cardiovascular diseases, which generally occur more frequently in men than in premenopausal women. There is a growing awareness that metabolic and immune dysfunction are intimately tied to the development of cardiovascular diseases. Thus, this review article focuses on sexual dimorphism in cardiovascular, metabolic, and immune function in health and disease, and was prepared for the journal Biology of Sex Differences as part of its recognition of "Sex Differences in Health Awareness Day." This article clearly reveals the striking importance of sex differences in cardiovascular, metabolic, and immune system functions in health and in the pathogenesis of disease processes, which likely involve a combination of effects of the sex chromosomes as well as the gonadal steroid hormones. In the developing fetus, fetal sex clearly influences the pathogenesis of the hypertensive diseases of pregnancy, and sex differences in the effects of the fetus continue beyond pregnancy and appear to influence the future risk of maternal cardiometabolic diseases. Similarly, there is strong evidence of many clinically-relevant sexually dimorphic characteristics of obesity and type 2 diabetes mellitus which appear to involve both chromosomal and humoral effects, although the underlying pathophysiological mechanisms are poorly understood. The gonadal steroid hormones (both androgens and estrogens) are known to exert important effects on the regulation of intermediary metabolism; however, recent studies reveal the emerging importance of these hormones in the regulation of inflammation. For example, menopausal declines in estrogen are associated with increases in inflammatory markers and the development of heart failure in women. Similar effects on inflammatory function may also occur in men with progressive age-dependent declines in testosterone. Declines in androgen levels in men are also associated with detrimental effects on cardiovascular and metabolic function, especially the development of metabolic syndrome and type 2 diabetes, important risk factors for cardiovascular disease. Interestingly, pathophysiological increases in the normally lower testosterone levels in women are associated with the same detrimental effects on cardiovascular and metabolic function, revealing striking bi-directional sex differences in the effects of the androgens. Finally, it is increasingly apparent that the kidney plays an important role in the regulation of sex steroid hormone levels, and the declines in both estrogen and testosterone that occur with chronic kidney disease appear to play an important role in the linkage between chronic kidney disease and the development of cardiovascular disease. In conclusion. It is clear that sex differences in cardiovascular, metabolic, and immune function play important roles in health and in the pathogenesis of disease. Elucidation of the chromosomal and humoral mechanisms underlying sexual dimorphism in physiological functions will play important roles in the future development of age- and sex-specific prevention and pharmacotherapy of disease processes.